A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4000-4000 ◽  
Author(s):  
D. Kerr ◽  
R. Gray ◽  
P. Quirke ◽  
D. Watson ◽  
G. Yothers ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Validation Study ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Cancer Tissue ◽  
Development Studies ◽  
Rt Pcr ◽  
Total N ◽  
Stage Ii Colon Cancer

4000 Background: New clinical tools are needed to improve risk assessment and treatment decisions in stage II colon cancer. Four development studies [Surgery (Sx) alone: NSABP C-01/C-02 (n=270) and CCF study (n=765); Sx+5FU/LV: NSABP C-04 (n=308) and C-06 (n=508)] were performed to select the genes for prediction of recurrence and 5FU/LV benefit. To determine clinical utility of the prespecified assay, we performed a large, independent, prospectively designed, clinical validation study in stage II colon cancer pts from the QUASAR trial. Methods: Gene expression was quantitated by RT-PCR from 30 μm manually microdissected fixed paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS) were analyzed using Cox regression. Results: Combined analysis of the four development studies (total n=1,851; 761 candidate genes) identified 48 genes significantly associated with recurrence risk and 66 genes predictive of 5FU/LV benefit. Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic recurrence score (RS) and predictive treatment score (TS) algorithms. In the QUASAR validation study, tumor blocks were collected for 68% of pts; 1,490 pts with blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV). Median FU=6.6 yrs. In the primary analysis of RFI in pts following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15–2.15; p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk increased monotonically with increasing RS. In multivariate analyses, RS retained prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31, 95% CI 0.15–0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35–2.79; p=0.005), together ∼25% of pts, also were independently prognostic. 5FU/LV benefit was significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19). Conclusions: The colon cancer recurrence score is a validated, independent predictor of individualized recurrence risk for stage II colon cancer patients following surgery. [Table: see text]

Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3512-3512 ◽  
Author(s):  
Michael O'Connell ◽  
Mark Lee ◽  
Margarita Lopatin ◽  
Greg Yothers ◽  
Kim Clark-Langone ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cox Regression ◽  
Cox Model ◽  
Disease Free Survival ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Rt Pcr ◽  
Relative Benefit ◽  
Stage Ii Colon Cancer

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.

A Validation Study for Recurrence Risk Stratification of Stage II Colon Cancer Using the 55-Gene Classifier

Oncology ◽  
2020 ◽  
Vol 98 (8) ◽  
pp. 534-541
Author(s):  
Eiji Shinto ◽  
Eiji Oki ◽  
Mototsugu Shimokawa ◽  
Shigeki Yamaguchi ◽  
Megumi Ishiguro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Risk Stratification ◽  
Validation Study ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Stage Ii Colon Cancer

scholarly journals Validation of the 12-Gene Colon Cancer Recurrence Score in NSABP C-07 As a Predictor of Recurrence in Patients With Stage II and III Colon Cancer Treated With Fluorouracil and Leucovorin (FU/LV) and FU/LV Plus Oxaliplatin

2013 ◽  
Vol 31 (36) ◽  
pp. 4512-4519 ◽  
Author(s):  
Greg Yothers ◽  
Michael J. O'Connell ◽  
Mark Lee ◽  
Margarita Lopatin ◽  
Kim M. Clark-Langone ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Therapy ◽  
Cox Regression ◽  
Cancer Recurrence ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Stage Iii ◽  
Treatment Benefit ◽  
Stage Ii Colon Cancer

Purpose Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Methods Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Results Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. Conclusion The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

A validation study of stratification by the 55-gene classifier for assessing recurrence risk in stage II colon cancer: The 55 STAR study (UMIN23879).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 3526-3526 ◽  
Author(s):  
Shigeki Yamaguchi ◽  
Kazuo Hase ◽  
Eiji Shinto ◽  
Eiji Oki ◽  
Mototsugu Shimokawa ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Validation Study ◽  
Recurrence Risk ◽  
Stage Ii ◽  
Stage Ii Colon Cancer

Validation Study of a Quantitative Multigene Reverse Transcriptase–Polymerase Chain Reaction Assay for Assessment of Recurrence Risk in Patients With Stage II Colon Cancer

2011 ◽  
Vol 29 (35) ◽  
pp. 4611-4619 ◽  
Author(s):  
Richard G. Gray ◽  
Philip Quirke ◽  
Kelly Handley ◽  
Margarita Lopatin ◽  
Laura Magill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Cox Proportional Hazards ◽  
Stage Ii ◽  
Treatment Benefit ◽  
Risk Of Recurrence ◽  
T Stage ◽  
Stage Ii Colon Cancer

Purpose We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. Patients and Methods We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. Results Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). Conclusion The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.

12-Gene Recurrence Score Assay Stratifies the Recurrence Risk in Stage II/III Colon Cancer With Surgery Alone: The SUNRISE Study

2016 ◽  
Vol 34 (24) ◽  
pp. 2906-2913 ◽  
Author(s):  
Takeharu Yamanaka ◽  
Eiji Oki ◽  
Kentaro Yamazaki ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Risk Group ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
High Risk Group ◽  
Stage Ii ◽  
Stage Iii ◽  
Stage Iiia ◽  
Resected Stage ◽  
Stage Ii Colon Cancer

Purpose The 12-gene Recurrence Score assay has been validated in resected stage II colon cancer treated with or without chemotherapy and resected stage III disease treated with chemotherapy. This study evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease. Methods A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II v III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. Results Overall, 597 of 630 patients were analyzable—247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25-unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% v 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%). Conclusion To our knowledge, this study provides the first validation of the 12-gene Recurrence Score assay in stage III colon cancer without chemotherapy and showed the heterogeneity of recurrence risks in stage III as well as in stage II colon cancer.

Effect of Oncotype DX colon cancer test results on treatment recommendations in patients with stage II colon cancer: Preliminary results.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 398-398
Author(s):  
Thomas H. Cartwright ◽  
Calvin Chao ◽  
Margarita Lopatin ◽  
Tanya GK Bentley ◽  
Michael Samuel Broder ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Adjuvant Treatment ◽  
Recurrence Score ◽  
Treatment Recommendations ◽  
Oncotype Dx ◽  
Stage Ii ◽  
Medical Oncologists ◽  
Stage Ii Colon Cancer ◽  
The Impact

398 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (N=277) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: As a planned preliminary analysis, we analyzed surveys from 92 eligible physicians. Physicians were more often in community (85%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 34–81). 84% of patients had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 2%, 14% and 84% of the time and 36% had comorbidities. Of the 60 patients tested for MMR/MSI, 9 (15%) were MMR-D or MSI-high and 37 (62%) were MMR-P or MSI-low; 14 (23%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 38 (41%) patients, observation in 35 (38%), and there was no recommendation in 19 (21%). For the 73 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 23 patients (32%), including changes from chemotherapy to observation and vice-versa. Conclusions: These preliminary findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results approximately one-third of the time. Final results will be reported to include accrual through December 2011.

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